P1274: IMPACT OF AUTOLOGOUS TRANSPLANT IN NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS TREATED WITH NOVEL TRIPLETS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Irina Amitai, Ronit Gurion, Pia Raanani, Iuliana Vaxman, Moshe Yeshurun, Hila Magen, Anat Gafter-Gvili, Liat Shargian
Journal: HemaSphere (2023)

Topic: 22. Stem cell transplantation - Clinical Background: High-dose therapy with melphalan followed by autologous stem cell transplant at the upfront setting (upfront ASCT) has significantly improved clinical outcomes of myeloma patients and become the standard of care for the past 30 years. However, with the advent of modern induction therapy, which for the last decade includes a combination of immunomodulatory and proteasome inhibitor drugs with corticosteroids (triplet therapy), the role of upfront ASCT approach has been called into question. Furthermore, increased life expectancy has led to renewed concerns about the association of ASCT with the long-term risk of secondary primary malignancies (SPMs). Several recent prospective studies have examined whether continuing with triplet therapy as consolidation with optional ASCT at relapse (standard-dose therapy, SDT), could result in comparable outcomes Aims:Methods: Systematic review and meta-analysis of randomized controlled trials comparing upfront ASCT vs. SDT approach among myeloma patients treated with triplet therapy as induction. Cochrane Library, PubMed, conference proceedings and references were searched until January 2023. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included progression free survival (PFS), safety, and SPMs. Subgroup analysis was conducted for high risk cytogenetics (defined by the presence of either 17p deletion, t(4;14) or t(14;16)). Results: Our search yielded three trials, conducted between 2010-2018, including 1,737 patients (all three were published in peer reviewed journals). Median age of patients ranged between 55-60 years. Median follow-up ranged between 44-76 months. Two trials evaluated bortezomib plus lenalidomide (VRd) induction followed by ASCT and 2 consolidation cycles vs. 8 VRd cycles. Third study tested carfilzomib plus lenalidomide (KRd) induction followed by ASCT and 4 consolidation cycles vs. 12 KRd cycles. Maintenance was given in all trails to both arms. There was no difference in OS between the arms, the pooled OS for upfront ASCT vs. SDT approach in all patients and in those with high-risk cytogenetics was HR 1.03 (95% CI, 0.85-1.26; I2 = 0%; 1,737 patients, 3 trials), and 0.85 (95% CI, 0.59-1.23; I2=0%; 222 patients, 2 trials), respectively. The pooled PFS for upfront ASCT vs. SDT was significantly improved in all the patients and in the high-risk cytogenetics subgroup, HR 0.67 [95% CI 0.59-0.76; I2 = 0%; 1,737 patients, 3 trials] and HR 0.59 [95% CI 0.44-0.7; I2 = 0%; 306 patients, 3 trials], respectively. Regarding safety, the risk of any grade 3-4 adverse events and grade 3-4 infections was higher in the upfront ASCT arm vs SDT approach, RR=1.17 [95% CI, 1.12-1.23; 1,737 patients] and RR=1.94 [95% CI, 1.49-2.52; 1,737 patients], respectively. The risk of secondary malignancies was reported in all three trials and was comparable between both arms. Two trials reported on secondary myeloid neoplasms, which were significantly higher among upfront ASCT arm vs SDT approach, HR 9.7 (1.8-52.25, I2=0%, 1422 patients). Summary/Conclusion: This systematic review and meta-analysis found that upfront ASCT approach in the era of triplet therapy results in significantly longer PFS among all patients, as well as the high-risk genetics subgroup, which is an unmet need. However, this did not translate into a survival benefit, regardless of cytogenetics risk. Moreover, upfront ASCT arm was associated with an increase rate of secondary myeloid neoplasms. In the current plethora of innovative therapies, the role of upfront ASCT is debatable.Keywords: Meta-analysis, Multiple myeloma, Autologous hematopoietic stem cell transplantation